HIV-infected patients are at increased risk for the development of emphysema; however the mechanisms associated with increased susceptibility have not been defined. Infectious agents may contribute to the development of emphysema by up-regulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to colonization by the opportunistic pathogen, Pneumocystis (Pc) is similar to that of emphysema, and is characterized by influx of CD8+ T cells, neutrophils and macrophages. We have shown a high frequency of colonization by Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc infection in simian immunodeficiency virus (SIV)-infected macaques. SIV/Pc co-infected monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. Obstructive pulmonary disease occurs prior to the onset of acute Pc pneumonia (PCP), is characterized by enlarged alveolar airspaces and is not responsive to bronchodilator challenge. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. In the primate model, we have a unique opportunity to test this hypothesis directly. The specific aims of this proposal are: 1) to test the hypothesis that Pc colonization in a model of AIDS leads to progressive loss of pulmonary function and development of AIDS-associated emphysema; 2) to elucidate the mechanisms whereby chronic inflammation induced by Pc colonization leads to tissue destruction and pulmonary function abnormalities; 3) to test the hypothesis that intervention in the course of Pc colonization in this model will ameliorate pulmonary damage. Relevance: Testing the hypothesis that Pneumocystis is a co-factor in the progression of HIV-associated emphysema is important because the information gained will lead to the development of intervention to prevent lung injury associated with Pc colonization obstructive lung damage.